Inflammatory bowel disease (IBD) is marked by the presence of chronic inflammation of the gastrointestinal tract. One form of the disease is ulcerative colitis, a disease that affects the large bowel exclusively and which is characterized by mucosal ulceration, superficial inflammatory-cell infiltration of the bowel wall, and in extensive long-standing cases, neoplastic transformation. Another form of the disease is termed Crohn's disease (regional enteritis or regional ileitis). Crohir's disease can affect any part of the alimentary canal, from the mouth to the rectum, although it is commonly involved in the terminal ileum and the ascending colon. It has been recently reported that long-standing ulcerative colitis in patients is correlated to an increased incidence of colorectal cancer. See, for example, Lennard-Jones, et al., Gut, 31:800-806 (1986); and Ekbom et al., N Engl. J. Med., 323:1228-1233 (1988). Furthermore, Crohn's disease has been firmly associated with an increased risk of colorectal cancer, Ekbom et al., Lancet, 336:357-359 (1990).
Approximately 10 percent of the cases involving either Crohn's disease or ulcerative colitis involve the same anatomic location, i.e., the large bowel. These two forms of inflammation are partly and possibly wholly distinct in their pathogenic events, however it also is likely that they share important common pathophysiologic processes. It was reported by odolsky, N. Engl. J. Med., 325 (13): 928-937 (1991), that certain cytokines are mediators of the inflammation, namely, interlieukin-1 (IL- 1) and interleukin-6 (IL-6). Along with IL-1 and IL-6, Stevens, et al., Dig. Dis. and Sciences, 37 (6):818-826 (1992), recently reported that the pro inflammatory cytokine tumor necrosis factor-alpha (TNF-(.alpha.) was expressed in the intestine of patients with IBD.
The most commonly used management agents for IBD include corticosteroids and sulfasalazine. Sulfasalazine is a congener of sulfapyridine and 5-aminosalycylic acid. Podlosky, N. Engl. J. Med., 325 (14): 1008-1016 (1991) reported that sulfasalazine acts, inter alia, as an inhibitor of prostaglandin synthase and 5-lipoxygenase. Sulfasalazine, while generally safe, is given to less than about 20 percent of the patients due to hypersensitivities such as rash, arthritis, pericarditis, pancreatitis and pleuritis. Corticosteroid use is somewhat limited by the considerable risk of side effects and potential complications. Additional drugs, such as clonidine, cromoglycate, chloroquine, interferon, and methotrexate are a few of the drugs described by Peppercorn as potential therapies for IBD in Ann. Int. Med. 112:50-60 (1990).
Another complication to effective treatment has been the delivery of medicament to the inflammatory site. The time during which an orally administered therapeutic material resides in the stomach is an important factor in terms of its absorption. Most drugs are optimally absorbed in the small intestine, and thus rapid gastric emptying can lead to early bioavailability of the drug. However, a prolonged bioavailability of the drug is possible through a delayed gastric emptying. Attempts have been made to prolong the residence time of drugs in transit through the gastrointestinal tract. A variety of slow-release formulations and controlled release formulations are well-known in the art, for example, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate phthalate.
A well known pH-sensitive material is alginate. Alginate is an anionic copolymer of 1,4-linked-.beta.-D-mannuronic acid and .alpha.-L-guluronic acid. Various forms of alginate are available commercially. Such forms are typically 60% 1,4-linked-.beta.-D-mannuronic acid and 40% .alpha.-L-guluronic acid; or 30% 1,4-linked-.beta.-D-mannuronic acid and 70% .alpha.-L- guluronic acid. Alginic acid can spontaneously form a translucent gel when associated with calcium ions in an acidic environment. The use of alginate gel systems for sustained release drug delivery systems has been documented. The advantages of using an alginate gel delivery system for an orally-administered drug stems from the fact that alginate is non-toxic when taken orally, alginate beads can protect acid-sensitive drugs from gastric fluids, and provide the controlled release of drug when exposed to acidic environments. Examples of combinations of various drugs with alginate include Stockwell, et al., J. Controlled Release, 3:167-175 (1986) wherein sodium alginate delivery systems for the cationic drugs caffeine, sodium salicylate and chlorpheniramine are described. Segi, et al., Chem. Pharm. Bull., 37:3092-3095 (1989) describe the cationic drug, propanolol, and its interaction with alginate gel beads. Another cationic drug, theophylline was examined with alginate gel beads by Bahkoo, et al., Proc. Int. Symp. Controlled Release Bio. Mater. 18:441-442 (1991).
The entrapment of proteinaceous materials has just recently been explored. The encapsulation of fibroblast growth factor-alpha (FGF), epidermal growth factor (EGF) transforming growth factor (TGF-.alpha.) in sodium alginate gel beads is described by Downs, et al., J. Cell Physiol., 152:422-429 (1992). Downs et al. observed that the amount of protein entrapped within the alginate bead is dependent on the protein's electrostatic interactions with the alginate anion.
In view of the above, there remains the need in the art for an effective medicament for IBD and an efficient means of delivering such medicament to the site of inflammation.